Open AccessNovel Approaches to Enhance the Specificity and Safety of Engineered T Cells
Author(s) -
V D Fedorov,
Michel Sadelain,
Christopher C. Kloss
Publication year - 2014
Publication title -
the cancer journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.825
H-Index - 89
eISSN - 1540-336X
pISSN - 1528-9117
DOI - 10.1097/ppo.0000000000000040
Subject(s) - chimeric antigen receptor , cd19 , antigen , cancer research , immunotherapy , cancer immunotherapy , genetically engineered , cancer , computational biology , computer science , medicine , biology , immunology , gene , biochemistry
T-cell therapies using engineered T cells show great promise for cancer immunotherapy, as illustrated by the CD19 paradigm. Much of the excitement about this approach, and second-generation CARs in particular, is due to the dramatic clinical results recently reported by a few centers, especially in acute lymphoblastic leukemia, and the applicability of this approach, in principle, to a wide range of cancers. Extending the use of CAR therapies to cancers other than B-cell malignancies will require selective tumor targeting with minimal or acceptable "on-target, off-tumor" effects. The identification of new CAR target antigens is thus one of the next big challenges to address. Recognizing the paucity of currently available tumor-specific targets, we have developed broadly applicable approaches to enhance the tumor selectivity and safety of engineered T cells. Here, we review 2 promising concepts. One is to improve tumor targeting based on combinatorial antigen recognition. The other uses receptors that provide antigen-specific inhibition, which we named iCARs, to divert T cells from the normal tissues one wants to protect.